Project Abstract Alzheimer's disease (AD) is currently an incurable neurodegenerative disease that affects over 35 million people worldwide, including 5.4 million individuals in the USA with a new case diagnosed every minute. Over the past two decades, one of the most significant developments in the AD research field has been the generation of mouse models of AD. Although these have provided significant insight into the mechanism of AD, the findings have not yet translated into the development of any new disease-modifying therapies for the human condition. Moreover, there is concern about the discordance of treating AD in people versus mice, which may be due the incomplete modeling of the disease in mice. Along these lines, all of the currently available models are based on the rarer autosomal dominant form of the disease, whereas the majority of AD cases are sporadic, whose onset may still be influenced by genetics that display reduced penetrance compared to the autosomal dominant cases. Hence, there is an urgent need to develop the next generation of mouse models that have high face, construct, and translational validity, which means these models should be more closely aligned with sporadic AD (sAD). Over the past several years, the facility of GWAS has produced a rapid expansion in the list of risk factor genes that are associated with sAD. Here we propose to use a transdisciplinary/team approach to develop the next generation of mouse models that model sAD so that they can be used for preclinical therapeutic testing. Our strategy is to use our recently developed humanized wild- type APPKI mouse as the platform for introducing human tau, followed by other GWAS-identified risk polymorphisms that enhance the risk of developing sAD. We propose to develop the next generation of AD preclinical mouse models using the latest innovations in gene editing technology (CRISPR/Cas9 technology) to produce new mouse models that more accurately represent sAD. We will phenotype the mice using state-of- the-art quantitative methodology and make direct comparisons to the human condition and capitalize on novel reagents that have been developed at UCI, including unique conformation specific antibodies that identify multiple distinct forms of pathology. We will determine gene expression changes via RNA-seq and epigenetic disruptions, alterations in neuronal connectivity in hippocampal circuits via whole-cell patch clamping combined with laser scanning photostimulation, as well as LTP, behavior and cognition, and longitudinal functional imaging. We will also conduct biomarker development by performing plasma lipidomic and metabolomic analyses. We will distribute all data in an expeditious and accessible form for dissemination and will provide detailed protocols for characterization of the models for the field. Lastly, we have established an exciting partnership with The Jackson Laboratory to conduct second site validation of observed phenotypes and to re- derive, cryopreserve and distribute all new animal models so that they can be widely distributed to investigators in the field. Achieving these goals will be transformative for the AD research field.